Cholesterol Metabolism

Study Notes

Cholesterol is a crucial steroid alcohol found in animal tissues.
It's a structural component of all cell membranes, influencing membrane fluidity.
Cholesterol is a precursor for bile acids, steroid hormones, and vitamin D.
The liver plays a central role in cholesterol homeostasis.
Cholesterol enters the liver from dietary sources and de novo synthesis by non-liver tissues and the liver.
Cholesterol exits the liver as unmodified cholesterol in bile or is converted into bile salts, secreted into the intestinal lumen.
Cholesterol also contributes to plasma lipoproteins directed to peripheral tissues.
In humans, cholesterol influx and efflux are not perfectly balanced, leading to gradual cholesterol deposition, primarily in the endothelial linings of blood vessels.
Lipid deposition causes plaque formation and blood vessel narrowing (atherosclerosis). This raises the risk of heart, brain, and peripheral vascular diseases.
Cholesterol synthesis sites include liver, adrenal cortex, testes, ovaries, and intestine.
All nucleated cells can synthesize cholesterol, including arterial walls.
Cholesterol synthesis enzymes exist in both endoplasmic reticulum and cytoplasm.

Bile is a watery mixture of organic and inorganic compounds.
Phosphatidylcholine (lecithin) and bile salts (conjugated bile acids) are the primary organic components.
Bile can either flow directly from the liver into the duodenum through the common bile duct, or be stored in the gallbladder until needed for digestion.
Intestine bacteria remove glycine and taurine from bile salts, regenerating bile acids.
Bacteria also convert primary bile acids to secondary bile acids (by removing a hydroxyl group). For example, deoxycholic acid is derived from cholic acid.

Bile salt deficiency leads to cholesterol gallstones, called cholelithiasis.
Cholesterol precipitates in the gallbladder due to decreased bile salt levels, or increased cholesterol.
Low bile acid and elevated cholesterol levels can cause gallstone formation.

HMG CoA reductase is a key regulatory enzyme for cholesterol synthesis.
Insulin and thyroid hormone increase HMG CoA reductase activity.
Cortisol and glucagon decrease this enzyme's activity.
Lovastatin and similar "statin" drugs inhibit HMG CoA reductase competitively to lower cholesterol levels.

Dietary fiber binds bile acids and increases their excretion, resulting in reduced bile acid recycling and consequently reduced cholesterol synthesis.
Gross malabsorption of bile acids in the intestine (especially in patients with severe ileal disease), biliary tract obstruction, and/or severe hepatic dysfunction (affects bile salt production), can also cause cholelithiasis.
Elevated biliary cholesterol excretion (such as with fibrate use) can also result in cholelithiasis.

Laparoscopic cholecystectomy (removing the gallbladder) is the typical treatment.
Oral chenodeoxycholic acid can dissolve gallstones for those who can't undergo surgery, but this takes months or years.